Evaluation of Capecitabine and (Chemo)Radiotherapy Versus Total Mesorectal Excision in Organ Preservation for Early Stage Rectal Cancer

The primary objective of the STAR-TREC study is to assess the feasibility of conducting a large, multi-centre randomized trial comparing radical surgery with organ-saving treatment using **(chemo)radiotherapy** followed by selective transanal microsurgery in patients with early stage colorectal cancer. This is clinically relevant as it aims to determine whether organ preservation strategies can be effectively implemented as a first-line treatment, potentially reducing the need for radical surgery and its associated morbidities.

Secondary objectives include:

• Evaluating the ability of international partners to procure independent funding and open the study to recruitment.
• Assessing the efficacy of organ-preserving treatment arms, with a focus on achieving an organ-saving rate greater than 50% at 12 months post-randomization.
• Determining the accuracy of MRI staging in patients undergoing primary TME surgery and its correlation with post-operative histological staging.
• Estimating the accuracy of MRI in predicting tumor response to radiotherapy in the organ-saving group.
• Comparing pelvic failure rates and overall survival rates between organ-saving treatments and primary TME surgery at 3 years.
• Measuring the proportion of patients with a stoma at 30 days and 12 months, and assessing health-related quality of life and dysfunctions using standardized tools.
• In Phase III, demonstrating the efficacy and safety of mesorectal radiation fields, establishing a standardized evaluation scheme for clinical response, and investigating genomic markers for patient selection.

The clinical trial involves a total of **200 participants** diagnosed with **early stage colorectal cancer**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including a biopsy-proven adenocarcinoma of the rectum and staging determined by MRI or Endorectal Ultrasound. The trial excludes vulnerable populations and requires participants to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate treatment strategies for organ preservation in early rectal cancer, with participants required to be willing and able to provide informed consent.

The clinical trial is designed to evaluate the feasibility and efficacy of organ-preserving strategies compared to radical surgery for **early stage colorectal cancer**. This is a phase II/III randomized, controlled, double-blind trial. The trial aims to assess whether a strategy involving (chemo)radiotherapy followed by selective transanal microsurgery can lead to higher organ preservation rates and improved quality of life compared to total mesorectal excision. The trial is expected to commence recruitment on November 1, 2024, and conclude by December 31, 2027.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as biopsy-proven adenocarcinoma of the rectum and specific staging requirements. Follow-up visits will be scheduled to monitor treatment response, assess acute treatment-related toxicity, and evaluate organ preservation outcomes. The primary endpoint for phase II is the recruitment rate at 12 and 24 months, while phase III focuses on the proportion of patients achieving successful organ preservation at 30 months. Secondary endpoints include clinician-reported toxicity, complete response rates, and various survival metrics up to 60 months.

The expected duration of participant involvement varies, with follow-up assessments extending up to 60 months post-treatment initiation. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events, or disease progression that necessitates alternative treatment. The trial employs **Capecitabine** Glenmark 150 mg film-coated tablets as part of the treatment regimen, administered orally. The maximum daily dose is 825 mg/m², with a total dose not exceeding 1650 mg/m² over a 25-day treatment period. The trial's design ensures rigorous monitoring and data collection to support the evaluation of organ-preserving strategies in early stage colorectal cancer.

The clinical trial involves the administration of **Capecitabine Glenmark 150 mg film-coated tablets** as the experimental medication. Capecitabine is a chemical substance classified under the ATC code L01BC06. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. The dosage regimen involves a maximum daily dose of 825 mg/m², with a total maximum dose of 1650 mg/m² over a treatment period of up to 25 days. The medication is not formulated for pediatric use and is manufactured by Glenmark Pharmaceuticals S.R.O. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as deemed necessary by the study protocol. These treatments will be administered according to the established guidelines and will serve as a control to evaluate the efficacy and safety of the experimental medication. Participant compliance with all treatment regimens will be closely monitored to maintain the integrity of the trial data.

Efficacy in the STAR-TREC clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for the phase II component is the recruitment rate, measured at 12 and 24 months. For the phase III component, the primary endpoint is the proportion of patients with successful organ preservation at 30 months from the start of (chemo)radiotherapy treatment. Secondary endpoints include clinician-reported acute treatment-related toxicity up to 30 days following completion of (chemo)radiotherapy, the proportion of patients with a complete response to (chemo)radiation therapy, and the proportion of patients undergoing transanal local excision. Additionally, time to event of organ loss, non-regrowth pelvic tumor control, metastasis-free survival, non-regrowth disease-free survival, and overall survival will be evaluated at various time points, including 36 and 60 months.

Secondary endpoints also incorporate analyses of patient-reported outcomes, such as symptomatic toxicity, health economics, and health-related quality of life (HRQoL), measured at 3, 12, 24, and 36 months compared to baseline using validated questionnaires. The trial will utilize a validated Decision Regret Scale questionnaire to assess decision regret at 24 months. These efficacy parameters will be collected and analyzed to determine the optimal radiation schedule for achieving the highest rate of organ preservation and the best quality of life after organ preservation in patients with early rectal cancer.